Our development, in 1971, of a photochemical route to fluorinated imidazoles has led to the synthesis of a wide variety of fluoro analogues of imidazole-based metabolites. Many of these compounds have shown interesting properties as agonists or antagonists and have proved useful as research tools and as possible chemotherapeutic agents. A striking difference has been found between 2-fluoro-L-histidine (2-FHIS) and the 4-fluoro isomer. While the former compound is readily incorporated into new protein in place of histidine (both in bacteria and mammals), the 4-fluoro isomer is not incorporated at all. Furthermore, 2-FHIS shows antibacterial, antiviral, antileukemic and antimalarial properties; again, the 4-fluoro shows none of these activities. We have become particularly interested in the antimalarial properties of 2-FHIS, since the compound is uniquely and selectively active against Plasmodium falciparum, that parasite which is notoriously resistant to chemotherapy. Of some 25 histidine analogues tested thus far, only two show useful antimalarial activity: 2-FHIS is selectively active against P. falciparum, while 2-IHIS shows broad-spectrum antimalarial activity. Surprisingly, neither 2-C1HIS nor 2-BrHIS are active and, thus, 2-FHIS and 2-IHIS may operate by different mechanisms. Laboratory-scale production of these histidine analogues is extremely time-consuming, involves multiple low-yield steps, and is limited to small batch operation. Our recent efforts to find alternative, and more economical, routes have been successful - at least for 2-IHIS. Readily available 2,4-diiodo-L-histidine can be converted into mixtures of 2-IHIS, 4-IHIS and HIS by photoreduction, catalytic hydrogenation or reduction with titanium trichloride. The last method is especially promising, providing yields of 2-IHIS up to 20% in this one-step process.